Susceptibility‐Guided Versus Empirical First‐Line Therapy of Helicobacter pylori Infection in Adults: A Systematic Review and Meta‐Analysis

ABSTRACT Background Antimicrobial resistance undermines empirical first‐line regimens for Helicobacter pylori . We compared susceptibility‐guided therapy (SGT) versus empirical therapy in adults receiving first‐line treatment, focusing on intention‐to‐treat (ITT) eradication. Materials and Methods We searched MEDLINE (PubMed), Web of Science, and Scopus from inception to 30 September 2025 for randomized controlled trials (RCTs) and non‐randomized comparative studies (NRS) in adults with confirmed H. pylori . Interventions included phenotypic (culture/E‐test) or genotypic (PCR) SGT applied to biopsy, stool, or gastric juice specimens; comparators were empirical regimens including bismuth quadruple therapy (BQT) and non‐BQT options. The primary outcome was ITT eradication. We pooled risk ratios (RR) with DerSimonian–Laird random‐effects, reported I 2 /τ 2 , and derived 95% prediction intervals (PI). Subgroups were prespecified by comparator family (BQT vs. other) and specimen/method. Multi‐arm studies combined empirical arms within family or split across distinct families. Results Forty‐two studies met inclusion criteria; all contributed ITT data. RCTs (k = 33) favored SGT over empirical therapy (pooled RR 1.09, 95% CI 1.05–1.13; I 2 73%; 95% PI 0.92–1.30). NRS (k = 12) were directionally consistent (pooled RR 1.15, 95% CI 1.10–1.22; I 2 75%; 95% PI 0.99–1.35). In RCTs, effects were neutral‐to‐modest vs. BQT (RR 1.03, 95% CI 0.97–1.10) and clearer vs. other empirical regimens (RR 1.12, 95% CI 1.06–1.18). Conclusions In adult first‐line therapy, SGT achieves at least non‐inferior—and often superior—eradication versus empirical regimens; the incremental benefit is attenuated where BQT is standard. These findings support selective, and increasingly justified, integration of susceptibility testing in settings with clinically relevant resistance.